Modified Vaccinia virus Ankara (MVA) is a highly attenuated vaccinia virus that cannot replicate in human cells. It is expected to have a better safety profile than the traditional smallpox vaccines. The clinical aspect of this project is a Phase I/II clinical trial of this investigational vaccine. The IND for this study agent was submitted to the FDA in the last fiscal year (8/14/02) and after IRB and FDA approval, the clinical study was initiated on 12/19/02. The clinical trial design is phase I/II, randomized, placebo-controlled, double-blinded, schedule-finding studies of MVA. The hypothesis is that MVA will be safe in humans when administered by intramuscular (IM) injection and will result in an immune response comparable to that observed after Dryvax primary vaccination. Subjects are being randomized to different primary immunization schedules either with Dryvax or with MVA or placebo. This is followed by Dryvax challenge 12 weeks after completion of the primary vaccination schedule. Safety evaluations are performed on an ongoing basis throughout the study and immunogenicity samples are collected and frozen for batch testing by research laboratories. Interim safety data were reviewed by the Intramural Data and Safety Monitoring Board on 6/9/03.